Functional annotation with expression validation identifies novel metastasis-relevant genes from post-GWAS risk loci in sporadic colorectal carcinomas (original) (raw)
2023, medRxiv (Cold Spring Harbor Laboratory)
Colorectal cancer (CRC) is the third highest incidence cancer and leading cause of cancer mortality 1 worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic 1 factors are unclear. This study aims to identify metastasis-relevant genes and pathways for better management of 1 metastasis-prone patients. Multiple lines of evidence have indicated that germline variants play important role in 1 shaping the somatic (tumor) genome. A case-case genome-wide association study comprising 2677 sporadic 1 Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human 1 SNP6 microarray platform and analyzed with the correlation/trend test based on the additive model. Single 1 nucleotide polymorphism (SNP) variants with association testing-log10p-value ≥ 5 were imported into 1 Functional Mapping and Annotation (FUMA) for functional annotation which uncovered glycolysis as the top 2 hallmark geneset. Transcripts from two of the five genes profiled, HAX1 and HMMR, were significantly down-2 regulated in the metastasis-positive tumors. In contrast to disease-risk variants with minimal impact on survival, 2 HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. 2 Furthermore, examining the subtype datasets with FUMA and Ingenuity Pathway identified distinct pathways 2 demonstrating sexual dimorphism in CRC metastasis. Combining genome-wide association testing with in 2 silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as 2 features to develop subtype-specific metastasis-risk signatures for tailored management of Stage I-III CRC 2 patients.
Loading Preview
Sorry, preview is currently unavailable. You can download the paper by clicking the button above.